T cells: the usual subsets

Chen Dong and Gustavo J. Martinez

T cells have important roles in immune responses and function by directly secreting soluble mediators or
through cell contact-dependent mechanisms. Many T cell subsets have been characterized. Although
effector T cells were originally considered to be terminally differentiated, a growing body of evidence has
challenged this view and suggested that the phenotype of effector T cells is not completely fixed but is
more flexible or plastic. T cells can have mixed phenotypes (that is, have characteristics usually
associated with more than one T cell subset) and can interconvert from one subset phenotype to another,
although instructive signalling can lead to long-term fixation of cytokine memory. T cell plasticity can be
important for adaptation of immune responses in different microenvironments and might be particularly
relevant for host defence against pathogens that colonize different tissues. Distinct T cell subsets, or
differentiation states, can be identified based on the cell surface markers expressed and/or the effector
molecules produced by a particular T cell population. This Poster summarizes our current understanding of
the surface markers, transcriptional regulators, effector molecules and functions of the different T cell
subsets that participate in immune responses. Further knowledge of how these T cell subsets are regulated
and cooperate with each other will provide us with better tools to treat immune-related diseases.

Cytotoxic T cell Exhausted T cell Anergic T cell TR1 cell Natural TReg cell NKT cell CD8 T cell
Surface TCR, CD3, CD8 Surface CD3, CD8, PD1, Surface TCR, CD3, BTLA Surface TCR, CD3, CD4 Surface phenotype TCR, CD3, CD4, CD25, CTLA4, GITR Surface phenotype NK1.1, SLAMF1, SLAMF6, TGFR, Surface or TCR, CD3,
phenotype phenotype TIM3, 1B11, LAG3 phenotype phenotype Transcription factors FOXP3, STAT5, FOXO1, FOXO3 V14, J18 (mouse) phenotype CD8, B220
Transcription EOMES, T-bet, BLIMP1 Transcription BLIMP1 Effector GRAIL, CBL-B, ITCH, NEDD4 Transcription Not known V24, J18 (human) Effector IL-10, TGF
Effector molecules secreted IL-10, TGF, IL-35
factors factors factors factors Transcription PLZF molecules
Function Mediate immunosuppression and tolerogenic responses factors secreted
Effector Perforin, granzyme, IFN Function Generated in response Function These cells are generated Effector IL-10 through contact-dependent and -independent
molecules to chronic antigen- following TCR activation in molecules mechanisms. These cells are generated in the thymus. Effector molecules IL-4, IFN, IL-17A Function Intraepithelial lymphocytes
secreted mediated TCR the absence of co-stimulatory secreted secreted are found in the gut. They can
Function Cytotoxic; kill infected and stimulation. These signals, which leads them Function Can have both pro- and anti-inflammatory develop intra- or extra-
cells express inhibitory to become unresponsive to Function Immunosuppression Inducible TReg cell thymically. They express or
transformed cells and thereby mediated by IL-10 functions. Have been shown to modulate immune
protect the host from viral receptors and lack subsequent stimulatory signals. Surface phenotype TCR, CD3, CD4, CD25, CTLA4, GITR responses in several different settings, including TCRs. TCR+ cells express
effector cytokine They are functionally inactive production. These cells
infections and cancer. Direct Transcription factors FOXP3, FOXO1, FOXO3, STAT5, SMAD2, SMAD3, SMAD4 cancer, autoimmunity, allergy, infection and graft- KGF, whereas TCR+ cells do
production; they cells and fail to proliferate or are generated from naive
killing is mediated by secretion of Effector molecules secreted versus-host disease. not. Most TCRs are
Tcells in the presence of IL-10, TGF
perforin and granzymes, which therefore fail to mount produce IL-2. Their generation enriched for self-reactivity.
TGF and IL-27 or in the Function Promote immunosuppression and tolerance by Other features SAP expression. CD1-restricted TCR.
cause apoptosis of target cells. effective antiviral may be important for avoiding They require 2 microglobulin-
presence of the immuno contact-dependent and -independent mechanisms. MAITcells express an invariant TCR -chain
immune responses. autoimmune responses. dependent MHC class I
Other In humans, mainly CD45RO+. Some suppressive drugs These cells are generated from naive T cells in the (V33J19 in mice; V7.2J19 in humans).
features terminally differentiated CTLs in Other Increased expression of p27KIP1, expression for their generation
vitamin D3 and periphery and, at least in some cases, TGF and IL-2 MAITcells are MR1 restricted (not CD1 restricted)
humans re-express CD45RA. features which leads to cell cycle arrest. and/or homeostasis. They can
dexamethasone. are important for their differentiation. but have similarities to NKT cells.
have regulatory functions
through the production of
IL-10 and TGF.

100m TCR CD8 CD4 TCR

CD4
TCR
TCR CTLA4 SLAMF1 TCR
CD3 Cytokine SLAMF6 CD8
CD8 PD1 TCR receptor CD3 Chemokine GITR CD3 TCR NK1.1 TGFR TCR
TIM3 1B11 receptor CD25 IL-7R CD3
80m BTLA B220
TCR CD62L LAG3 CD44 CD3 CD3
CD3 CD3
IL-7R CD3
CCR7 CCR7
60m

40m
Naive Cytotoxic Exhausted Anergic Helper Regulatory Memory NKT CD8

CD4+ T cell TH1 cell TH17 cell Central memory T cell T cell
Surface phenotype TCR, CD3, CD4, CCR7, CD62Lhi, IL-7R (CD127) Surface phenotype TCR, CD3, CD4, IL-12R, IFNR, CXCR3 Surface phenotype TCR, CD3, CD4, IL-23R, CCR6, IL-1R, Surface phenotype CCR7hi, CD44, CD62Lhi, TCR, CD3, Surface TCR, CD3
CD161 (human only) IL-7R (CD127), IL-15R phenotype
Transcription THPOK Transcription factors T-bet, STAT4, STAT1
factors Transcription factors RORt, STAT3, ROR Transcription factors BCL-6, BCL-6B, MBD2, BMI1 Effector IFN, IL-17A, IL-17F, IL-22
Effector molecules secreted IFN, IL-2, LT
Effector molecules IL-2, CD40L molecules
Function Patrol through lymph nodes scanning peptide Function Promote protective immunity against intracellular pathogens. By secreting Effector molecules secreted IL-17A, IL-17F, IL-21, IL-22, CCL20
secreted Low levels IL-4, IFN, IL-17A secreted
MHC classII molecule complexes on APCs for IFN, they induce activation of macrophages and upregulation of iNOS, Function Promote protective immunity against extracellular bacteria and fungi,
the presence of their cognate antigen. Following Function Preferentially reside in secondary lymphoid Function Enriched at epithelial surfaces
leading to the killing of intracellular pathogens such as Leishmania major, mainly at mucosal surfaces. Also promote autoimmune and inflammatory
activation by APCs, naive CD4+ Tcells organs, mounting recall responses to and can have both pro- and
Listeria monocytogenes and Mycobacterium spp. Their development is diseases. Generated in the presence of TGF and IL-6 and/or IL-21 and are
differentiate into effector or regulatory Tcells; antigens. Even though these cells lack anti-inflammatory functions,
regulated by IL-12. maintained by IL-23 and IL-1.
activated naive T cells also give rise to memory immediate effector functions, they rapidly depending on the TCR
Other features Also express BATF, IB, IRF4 and AHR transcription factors. Human TH17 cells and the context. Have
T cells. proliferate and differentiate into effector
TH2 cell also produce IL-26. characteristics of both innate
Other features CD45RA expressed by human cells. Tcells following antigen stimulation.
Surface phenotype TCR, CD3, CD4, IL-4R, IL-33R, CCR4, IL-17RB, CRTH2 and adaptive immunity.
Transcription factors GATA3, STAT6, DEC2, MAF
TH22 cell Effector memory T cell Other IFN- and IL-17A-producing
CD8+ T cell
Surface phenotype TCR, CD3, CD4, CCR10 features cells are distinct populations
Surface phenotype TCR, CD3, CD8, CCR7, CD62Lhi, IL-7R (CD127) Effector molecules secreted IL-4, IL-5, IL-13, IL-10 Surface phenotype CD62Llow, CD44, TCR, CD3, IL-7R (CD127),
Transcription factors AHR that can be distinguished by
Function Promote humoral immune responses and host defence against extracellular IL-15R, CCR7low
Transcription RUNX3 CD27 and CCR6 expression.
parasites. However, they can also potentiate allergic responses and asthma. Effector molecules secreted IL-22 Transcription factors BLIMP1 Innate immune recognition by
factors
Their development and maintenance is regulated by IL-4, IL-25 and IL-33. Function Identified in inflammatory skin diseases. Their role in host defence remains Effector molecules Rapid and high production of inflammatory expression of TLRs.
Function Patrol through lymph nodes scanning peptide
Other features IRF4 is also an important transcription factor. unclear as this subset has only recently been characterized. Their identity as an secreted cytokines
MHC class I molecule complexes for the
independent TH cell subset needs to be confirmed.
presence of their cognate antigen. Following Function Preferentially found in peripheral tissues.
activation by APCs, they differentiate into TH9 cell They provide immediate protection upon
CTLsand memory T cells. TFH cell antigen challenge through, for example, the
Surface phenotype TCR, CD3, CD4
Other features CD45RA expressed by human cells. Surface phenotype TCR, CD3, CD4, CXCR5, SLAM, OX40L, CD40L, ICOS, IL-21R, PD1 rapid production of effector cytokines.
Transcription factors PU.1
Transcription factors BCL-6, STAT3
Effector molecules secreted IL-9, IL-10
Effector molecules secreted IL-21
Function Involved in host defence against extracellular parasites, primarily
nematodes. Despite their production of anti-inflammatory IL-10, they Function These cells are involved in promotion of germinal centre responses and
promote allergic inflammation. Their role in other inflammatory diseases provide help for Bcell class switching.
still remains unclear as this subset has only recently been characterized. Other features SAP expression.

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Abbreviations
AHR, aryl hydrocarbon receptor; APC, antigen-presenting cell; BATF, basic leucine zipper
transcription factor, ATF-like; BCL-6, B cell lymphoma 6; BLIMP1, B lymphocyte-induced maturation
protein 1; BTLA, B and T lymphocyte attenuator; CBL-B, Casitas B-lineage lymphoma B;
CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CRTH2, chemoattractant receptor-
homologous molecule expressed on TH2 cells; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic
Tlymphocyte antigen 4; CXCR, CXC-chemokine receptor; EOMES, eomesodermin; FOX,
forkhead box; GATA3, GATA-binding protein 3; GITR, glucocorticoid-induced TNF-receptor-
related protein; GRAIL, gene related to anergy in lymphocytes; IB, inhibitor of NF-B-; ICOS,
inducible T cell co-stimulator; IFN, interferon-; IL, interleukin; iNOS, inducible nitric oxide
synthase; IRF4, interferon-regulatory factor 4; ITCH, itchy homologue E3ubiquitin protein ligase;
J, joining region; KGF, keratinocyte growth factor; L, ligand; LAG3,lymphocyte activation gene 3; Affiliations
LT, lymphotoxin-; MAF, musculoaponeurotic fibrosarcoma oncogene; MAIT, mucosal-associated Chen Dong and Gustavo J. Martinez are at the
invariant T; MBD2, methyl-CpG-binding domain protein 2; MR1, MHC-related protein1; NEDD4, Department of Immunology, M.D. Anderson Cancer
neuronal precursor cell-expressed developmentally downregulated 4; NKT, natural killer T; Center and Graduate School of Biomedical Sciences,
p27KIP1, p27 kinase inhibitory protein 1; PD1, programmed cell death1; PLZF, promyelocytic University of Texas Health Science Center at Houston,
leukaemia zinc-finger; R, receptor; ROR, retinoic acid receptor-related orphan receptor; RUNX3, Houston, Texas 77030, USA.
Runt-related transcription factor 3; SAP, SLAM-associated protein; SLAM, signalling lymphocytic
activation molecule; SMAD, mothers against decapentaplegic homologue; STAT, signal transducer Edited by Yvonne Bordon; copyedited by Gemma Ryan;
and activator of transcription; TCR, T cell receptor; TFH, Tfollicular helper; TGF, transforming designed by Simon Bradbrook.
growth factor-; THPOK, TH-inducing POZ/Kruppel-like factor; TH, T helper; TIM3, Tcell 2010 Nature Publishing Group.
immunoglobulin domain and mucin domain protein 3; TLR, Toll-like receptor; V, variable region. http://www.nature.com/reviews/posters/Tcellsubsets

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